Dataset Information

Outcomes and surgical management of persistent fetal vasculature.

ABSTRACT:

Objective

To analyse outcomes in different forms of persistent fetal vasculature (PFV).

Methods and analysis

Retrospective cohort study at a university-based practice of children presenting with PFV between 2011 and 2020. Exclusion criteria was surgical management outside of our institution and follow-up less than 1 month. Wilcoxon and Student's t-tests were used for statistical analysis.

Results

Forty-six eyes of 45 patients presented with PFV at 16.7±31.3 (median 2.8) months old with 32.6±29.8 (median 22.5) months of follow-up. Types of PFV included: mild combined anterior-posterior (23 eyes, 50%), severe combined anterior-posterior (18 eyes, 39%), severe anterior (3 eyes, 7%), mild anterior (1 eye, 2%) and posterior (1 eye, 2%). Thirty-two eyes (70%) underwent PFV surgical correction; lensectomy (13 mild combined), vitrectomy (3 mild combined), sequential lensectomy then vitrectomy (3 severe combined), combined lensectomy-vitrectomy (11 severe anterior or severe combined), laser retinopexy (1 mild combined). Five eyes required additional vitrectomy surgery for retinal detachment, fold or cyclitic membrane. Nine eyes developed glaucoma, six requiring Intraocular pressure (IOP)-lowering surgery. At final follow-up, 32 eyes had at least form vision and 6 eyes were aversive to light. Eight eyes, all which were severe combined, and four that did not undergo PFV surgery, were unable to detect light due to phthisis bulbi (7) and optic nerve hypoplasia (1).

Conclusions

Classification of PFV is important in determining surgical approach with severe cases often requiring both lensectomy and vitrectomy for optimal anatomic and functional outcomes.

SUBMITTER: Khandwala N

PROVIDER: S-EPMC8094357 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Persistent fetal vasculature (PFV) is a human disease that results from failure of the fetal vasculature to regress normally. The regulatory mechanisms responsible for fetal vascular regression remain obscure, as does the underlying cause of regression failure. However, there are a few animal models that mimic the clinical manifestations of human PFV, which can be used to study different aspects of the disease. One such model is the Nuc1 rat model that arose from a spontaneous mutation in the Cryba1 (crystallin, beta 1) gene and exhibits complete failure of the hyaloid vasculature to regress. Our studies with the Nuc1 rat indicate that macroautophagy/autophagy, a process in eukaryotic cells for degrading dysfunctional components to ensure cellular homeostasis, is severely impaired in Nuc1 ocular astrocytes. Further, we show that CRYBA1 interacts with EGFR (epidermal growth factor receptor) and that loss of this interaction in Nuc1 astrocytes increases EGFR levels. Moreover, our data also show a reduction in EGFR degradation in Nuc1 astrocytes compared to control cells that leads to over-activation of the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway. The impaired EGFR-MTORC1-autophagy signaling in Nuc1 astrocytes triggers abnormal proliferation and migration. The abnormally migrating astrocytes ensheath the hyaloid artery, contributing to the pathogenesis of PFV in Nuc1, by adversely affecting the vascular remodeling processes essential to regression of the fetal vasculature. Herein, we demonstrate in vivo that gefitinib (EGFR inhibitor) can rescue the PFV phenotype in Nuc1 and may serve as a novel therapy for PFV disease by modulating the EGFR-MTORC1-autophagy pathway.AbbreviationsACTB: actin, beta; CCND3: cyclin 3; CDK6: cyclin-dependent kinase 6; CHQ: chloroquine; COL4A1: collagen, type IV, alpha 1; CRYBA1: crystallin, beta A1; DAPI: 4'6-diamino-2-phenylindole; EGFR: epidermal growth factor receptor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary growth factor; KDR: kinase insert domain protein receptor; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MKI67: antigen identified by monoclonal antibody Ki 67; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP: poly (ADP-ribose) polymerase family; PCNA: proliferating cell nuclear antigen; PFV: persistent fetal vasculature; PHPV: persistent hyperplastic primary vitreous; RPE: retinal pigmented epithelium; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase, polypeptide 1; SQSTM1/p62: sequestome 1; TUBB: tubulin, beta; VCL: vinculin; VEGFA: vascular endothelial growth factor A; WT: wild type.

Project description:PurposePersistent fetal vasculature (PFV) is a pathological condition accounting for 4.8% of children's blindness in the United States. However, the PFV cell composition and pathogenetic mechanisms are poorly understood. This study aims to characterize PFV cell composition and associated molecular features and attempts to lay a foundation for further understanding the disease.MethodsImmunohistochemistry was conducted to characterize cell types at the tissue level. Single-cell RNA sequencing (sc-RNAseq) was performed on the vitreous cells derived from normal and Fz5 mutant mice at two early postnatal ages and human PFV samples. Bioinformatic tools were used to cluster cells and analyze their molecular features and functions.ResultsThe findings of this study are as follows: (1) a total of 10 defined and one undefined cell types were characterized in both the hyaloid vessel system and PFV by sc-RNAseq and immunohistochemistry; (2) neural crest-derived melanocytes, astrocytes, and fibroblasts were specifically retained in the mutant PFV; (3) Fz5 mutants were found to possess more vitreous cells at early postnatal age 3 but returned to similar levels as the wild type at postnatal age 6; (4) altered phagocytic and proliferation environments and cell-cell interactions were detected in the mutant vitreous; (5) the human PFV samples shared fibroblast, endothelial and macrophage cell types with the mouse, but having distinct immune cells including T cells, NK cells and Neutrophils; and last, (6) some neural crest features were also shared between certain mouse and human vitreous cell types.ConclusionsWe characterized PFV cell composition and associated molecular features in the Fz5 mutant mice and two human PFV samples. The excessively migrated vitreous cells, intrinsic molecular properties of these cells, phagocytic environment, and cell-cell interactions may together contribute to PFV pathogenesis. Human PFV shares certain cell types and molecular features with the mouse.